Few, if any, patients with advanced stage follicular low grade NHL (FL) are cured with conventional treatment strategies. Following relapse the majority of these patients still respond to re-institution of treatment, however most will ultimately succumb to their disease. Over the past 10 years, we and others have attempted to cure relapsed and newly diagnosed patients with FL using ABMT. Although a subgroup of these patients clearly benefit from this approach, a significant percentage of patients relapse and/or experience complications of this procedure. The objective of this proposal is to attempt to study the biology of follicular lymphoma and attempt to translate these observations to the clinic to improve outcome while minimizing toxicity. It is presently unknown which biologic parameters govern the sensitivity of subpopulations of FL cells to treatment. Clinical, we observe extraordinary heterogeneity with regard disease presentation, rate of tumor progression, and heterogeneity of response to treatment. We propose to examine two major areas with regard to the biologic of FL. Second, to understand at a molecular level, why subpopulations of FL cells are resistant to treatment in vitro and then potentially in vivo. Therefore, the primary goal of this Project will be to identify which signals regulate follicular lymphoma growth and resistance to treatment. To this end, we propose three Specific Aims. First, we plan to continue our ongoing treatment protocols which focus ont he use of myeloablative therapy and anti-B cell mAb treated autologous hematopoietic stem cell support and immunotoxin therapy of minimal residual disease. Moreover, we plan to pilot new translational strategies including intensification of induction and ablative therapy, synergy of immunotoxins with chemotherapy, and treatment of minimal residual disease with immunotoxins, cytokines, and immunization based treatment strategies. Second, we plan to develop and optimize systems to growth FL cells in culture to study the heterogeneity of this neoplasm. Once technology is optimized, we plan to determine which microenvironment influences affect FL cell growth and survival, and which molecular signals regulate these observation. Third, we plan to examine the expression of survival genes in FL and to determine whether these molecules are responsible for the observed resistance. Again, attempts to modulate these pathways might provide translational strategies to alter treatment. The success of this Project is highly interdependent on determining which patients have minimal residual disease in the marrow or in the patient and methods to treat minimal residual disease.